Rational design, molecular docking, dynamic simulation, synthesis, PPAR-γ competitive binding and transcription analysis of novel glitazones

• Four novel glitazones (G1-G4) were designed for PPAR-γ receptor binding. • PPAR-γ competitive binding analysis proved compounds explicitly bound to PPAR-γ LBD. • Cytotoxicity assessment resulted in the nontoxic nature of all compounds. • G3 & G4 compounds possess dose-dependent PPAR-γ transcriptional activity. Over the last decade, peroxisome proliferator-activated receptor (PPAR-γ) has emerged as one of the important therapeutic targets in several metabolic and neurodegenerative disorders. The remarkable progress in drug discovery has resulted in designing novel PPAR-γ activators. Thiazolidinediones, also known as glitazones, have been demonstrated to play a significant role in treating several neurodegenerative diseases, diabetes, and cancer. Despite its wide range of adverse effects, glitazones orchestrate significant pharmacological activities. In this backdrop, we designed and synthesised novel glitazones for potential PPAR-γ binding activity. The synthesised novel compounds were structurally analysed using 1 H NMR, 13 C NMR and FT-IR. The interaction binding modes, binding free energy, and crucial amino acids involved in interactions of designed compounds with the target protein were studied using molecular docking. Further, molecular dynamic modeling was used to evaluate the stability of the best-docked complexes. TR-FRET, an in vitro PPAR-γ competitive binding assay, was performed to confirm the affinity of the well-docked compounds for the target protein. It demonstrated that the compounds explicitly bind to the PPAR-γ ligand-binding domain to exhibit pharmacological activity. The cytotoxicity of synthesised compounds was performed and confirmed the PPAR-γ transcription activity on SH-SY5Y cell lines